Genome-wide translational responses to stress: a focus on ribosome stalling

全基因组对压力的翻译反应：关注核糖体停滞

• 批准号: BB/Y000080/1
• 负责人: Juan Mata
• 金额: $ 80.67万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY000080%2F1
• 关键词: Genome; wide; translational; responses; stress

Genome-wide translational responses to stress: a focus on ribosome stallingOur bodies are made of very different types of cells: Skin cells are flat and protect our body, while brain cells have cables that pass messages around. Despite being so different, all our cells carry exactly the same information in their genes. What makes them special is what information they use, that is, which genes they switch on and off.Cells need to respond to changes in their environment (stress) to avoid damage or even death. Stress conditions include high or low temperatures, lack of nutrients or a poor supply of oxygen. Cells react to stress by varying the way in which they use the information from their genes.The information on how to make a cell is stored in the form of a DNA molecule. However, this information cannot be read directly: it first needs to be copied into another molecule called messenger RNA (mRNA), from which it can be 'translated' into a protein. Proteins are the components that directly build the cell and make it function, and it is also proteins that are responsible for protecting the cell from the damage caused by stress. The composition of a protein is stored ('encoded') in the messenger RNA. The translation from the messenger RNA to the protein follows a pattern called the genetic code.Cells react to stress by switching on 'defence' genes and by switching off the genes that are not needed during the response to stress. The process of turning on and off genes often takes place at the level of the translation of messenger RNAs (that is, by selecting which messenger RNAs will be translated into proteins).Translation is performed by tiny machines within the cells called ribosomes. Ribosomes are made of two parts (subunits). The two subunits are separate from each other, and get together onto a messenger RNA to translate it (i.e., to read it). Studying translation is relevant for human cells, because the mechanisms that regulate translation often go awry during cancer and several inherited conditions.The process of translating a messenger RNA can be divided into three phases, called initiation, elongation and termination. Initiation involves the two subunits binding together to a messenger RNA and start translating (reading it). After that, the two subunits move along the messenger RNA as they read it (elongation) until they reach the end (termination). Translation is often regulated at the place of initiation (i.e., by deciding which mRNAs get translated). However, translation can also be regulated at the level of elongation, usually by 'freezing' the ribosomes on the messenger RNA and stopping the reading process. This phenomenon is called ribosome 'stalling'.One way to study a complicated process of the human body is to use a model organism: this is a simpler creature, but similar enough to allow us to learn about ourselves. In my laboratory, we study a simple yeast -made of a single cell- that can react to many different types of stress. Using this yeast, we have discovered that when cells get stressed, they stop the process of elongation at specific positions of the messenger RNA. Interestingly, the position where the ribosomes stall is different depending on the kind of nutrients available to them. We would like to understand if this kind of stalling happens in other situations (we have tried 3), how the ribosomes 'know' where and when to stop, and how this behaviour is beneficial for a cell. We expect this information will be useful to understand how human cells behave and, eventually, help us devise cures for disease.

全基因组对压力的翻译反应：对核糖体档位的重点是由非常不同类型的细胞组成的：皮肤细胞平坦并保护我们的身体，而脑细胞的电缆则传递信息。尽管是如此不同，但我们所有的细胞都在其基因中具有完全相同的信息。使它们与众不同的是他们使用的信息，即他们打开和关闭的基因。细胞需要响应其环境变化（压力）以避免损坏甚至死亡。压力条件包括高温或低温，缺乏营养或氧气供应不足。细胞通过改变使用基因中信息的方式来反应应力。有关如何制造细胞的信息以DNA分子的形式存储。但是，无法直接读取此信息：首先需要复制到另一个称为Messenger RNA（mRNA）的分子中，可以将其“转换”到蛋白质中。蛋白质是直接构建细胞并使其发挥作用的成分，也是蛋白质负责保护细胞免受压力损害的损害。蛋白质的组成存储在信使RNA中。从信使RNA到蛋白质的翻译遵循一种称为遗传密码的模式。细胞通过打开“防御”基因并关闭对压力响应期间不需要的基因来反应压力。打开和关闭基因的过程通常发生在Messenger RNA的翻译水平上（也就是说，通过选择哪个Messenger RNA将转换为蛋白质）。译文在称为核糖体的细胞中执行的tiny机器。核糖体由两个部分（亚基）组成。这两个亚基是彼此分开的，并聚集在信over rna上以翻译它（即阅读）。研究翻译与人类细胞有关，因为调节翻译的机制通常在癌症和几种遗传条件下出现问题。翻译信使RNA的过程可以分为三个阶段，称为启动，伸长和终止。启动涉及两个亚基结合在一起，并开始翻译（阅读）。之后，两个亚基在读取信使RNA（伸长）时沿着信使RNA移动，直到到达末端（终止）。翻译通常在启动位置受到调节（即，通过确定mRNA被翻译）。但是，通常也可以通过“冷冻”信使RNA上的核糖体并停止阅读过程来调节翻译。这种现象称为核糖体“失速”。研究人体复杂过程的一种方法是使用模型有机体：这是一个更简单的生物，但足够相似，可以让我们学习自己。在我的实验室中，我们研究了单个细胞的简单酵母 - 可以对许多不同类型的压力做出反应。使用这种酵母，我们发现，当细胞受到压力时，它们会在信使RNA的特定位置停止伸长过程。有趣的是，核糖体摊位的位置不同，具体取决于他们可用的营养。我们想了解这种失速是否在其他情况下发生（我们尝试过3），核糖体如何“知道”何时和何时停止以及这种行为如何对细胞有益。我们希望这些信息对于了解人类细胞的行为方式，并最终帮助我们设计疾病的治疗方法将是有用的。